Lanzotred Drug Interactions

Potential for other medicinal products to affect enzalutamide exposures: CYP2C8 inhibitors: CYP2C8 plays an important role in the elimination of enzalutamide and in the formation of its active metabolite. Following oral administration of the strong CYP2C8 inhibitor gemfibrozil (600 mg twice daily), the AUC of enzalutamide increased while Cmax of enzalutamide decreased. For the sum of unbound enzalutamide plus the unbound active metabolite, the AUC increased while Cmax decreased. Strong inhibitors (e.g. gemfibrozil) of CYP2C8 are to be avoided or used with caution during enzalutamide treatment. If patients must be co-administered a strong CYP2C8 inhibitor, the dose of enzalutamide should be reduced to 80 mg once daily.
CYP3A4 inhibitors: CYP3A4 plays a minor role in the metabolism of enzalutamide. Following oral administration of the strong CYP3A4 inhibitor itraconazole (200 mg once daily), the AUC of enzalutamide increased while Cmax was unchanged. For the sum of unbound enzalutamide plus the unbound active metabolite, the AUC increased while Cmax was again unchanged. No dose adjustment is necessary when Lanzotred is co-administered with inhibitors of CYP3A4.
CYP2C8 and CYP3A4 inducers: Following oral administration of the moderate CYP2C8 and strong CYP3A4 inducer rifampin (600 mg once daily), the AUC of enzalutamide plus the active metabolite decreased while Cmax remained unchanged. No dose adjustment is necessary when Lanzotred is co-administered with inducers of CYP2C8 or CYP3A4.
Potential for enzalutamide to affect exposures to other medicinal products: Enzyme induction: Enzalutamide is a potent enzyme inducer and increases the synthesis of many enzymes and transporters; therefore, interaction with many common medicinal products that are substrates of enzymes or transporters is expected. The reduction in plasma concentrations can be substantial, and lead to lost or reduced clinical effect. There is also a risk of increased formation of active metabolites. Enzymes that may be induced include CYP3A in the liver and gut, CYP2B6, CYP2C9, CYP2C19, and uridine 5'-diphospho-glucuronosyltransferase (UGTs - glucuronide conjugating enzymes). The transport protein P-gp may also be induced, and probably other transporters as well, e.g. multidrug resistance-associated protein 2 (MRP2), breast cancer resistant protein (BCRP) and the organic anion transporting polypeptide 1B1 (OATP1B1).
It is shown that enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Co-administration of enzalutamide (160 mg once daily) with single oral doses of sensitive CYP substrates in prostate cancer patients resulted in a decrease in the AUC of midazolam (CYP3A4 substrate), a decrease in the AUC of S-warfarin (CYP2C9 substrate), and a decrease in the AUC of omeprazole (CYP2C19 substrate). UGT1A1 may have been induced as well. In patients with metastatic CRPC, Enzalutamide (160 mg once daily) had no clinically relevant effect on the pharmacokinetics of intravenously administered docetaxel (75 mg/m² by infusion every 3 weeks). The AUC of docetaxel decreased while Cmax decreased.
Interactions with certain medicinal products that are eliminated through metabolism or active transport are expected. If their therapeutic effect is of large importance to the patient, and dose adjustments are not easily performed based on monitoring of efficacy or plasma concentrations, these medicinal products are to be avoided or used with caution. The risk for liver injury after paracetamol administration is suspected to be higher in patients concomitantly treated with enzyme inducers.
Groups of medicinal products that can be affected include, but are not limited to: Analgesics (e.g. fentanyl, tramadol); Antibiotics (e.g. clarithromycin, doxycycline); Anticancer agents (e.g. cabazitaxel); Antiepileptics (e.g. carbamazepine, clonazepam, phenytoin, primidone, valproic acid); Antipsychotics (e.g. haloperidol); Antithrombotics (e.g. acenocoumarol, warfarin, clopidogrel); Beta-blockers (e.g. bisoprolol, propranolol); Calcium channel blockers (e.g. diltiazem, felodipine, nicardipine, nifedipine, verapamil); Cardiac glycosides (e.g. digoxin); Corticosteroids (e.g. dexamethasone, prednisolone); HIV antivirals (e.g. indinavir, ritonavir); Hypnotics (e.g. diazepam, midazolam, zolpidem); Immunosuppressant (e.g. tacrolimus); Proton pump inhibitor (e.g. omeprazole); Statins metabolized by CYP3A4 (e.g. atorvastatin, simvastatin); Thyroid agents (e.g. levothyroxine).
The full induction potential of enzalutamide may not occur until approximately 1 month after the start of treatment, when steady-state plasma concentrations of enzalutamide are reached, although some induction effects may be apparent earlier. Patients taking medicinal products that are substrates of CYP2B6, CYP3A4, CYP2C9, CYP2C19, or UGT1A1 should be evaluated for possible loss of pharmacological effects (or increase in effects in cases where active metabolites are formed) during the first month of enzalutamide treatment, and dose adjustment should be considered as appropriate. In consideration of the long half-life of enzalutamide (5.8 days), effects on enzymes may persist for one month or longer after stopping enzalutamide. A gradual dose reduction of the concomitant medicinal product may be necessary when stopping enzalutamide treatment.
CYP1A2 and CYP2C8 substrates: Enzalutamide (160 mg once daily) did not cause a clinically relevant change in the AUC or Cmax of caffeine (CYP1A2 substrate) or pioglitazone (CYP2C8 substrate). The AUC of pioglitazone increased while Cmax decreased. The AUC and Cmax of caffeine decreased. No dose adjustment is indicated when a CYP1A2 or CYP2C8 is co-administered with Lanzotred.
P-gp substrates: It is indicated that enzalutamide may be an inhibitor of the efflux transporter P-gp. The effect of enzalutamide on P-gp substrates has not been evaluated; however, under conditions of clinical use, enzalutamide may be an inducer of P-gp via activation of the nuclear pregnane receptor (PXR).
Medicinal products with a narrow therapeutic range that are substrates for P-gp (e.g. colchicine, dabigatran etexilate, digoxin) should be used with caution when administered concomitantly with Lanzotred and may require dose adjustment to maintain optimal plasma concentrations.
BCRP, MRP2, OAT3 and OCT1 substrates: Based on data, inhibition of BCRP and MRP2 (in the intestine), as well as organic anion transporter 3 (OAT3) and organic cation transporter 1 (OCT1) (systemically) cannot be excluded. Theoretically, induction of these transporters is also possible, and the net effect is presently unknown.
Effect of food on enzalutamide exposures: Food has no clinically significant effect on the extent of exposure to enzalutamide. In current available data, Enzalutamide was administered without regard to food.